The burden of cardiovascular disease is increasing in both developed and developing countries. This relates to an acceleration in the incidence of diabetes and obesity as well as to other cardiovascular risk factors, including hypercholesterolaemia, hypertension and smoking. All these conditions have in common a mechanism of vascular abnormality termed endothelial dysfunction (Rubanyi, 1993).
Nitric oxide (NO), a chemically unstable radical formed by enzymatic conversion of L-arginine in the presence of molecular oxygen, elicits relaxation of vascular smooth muscle cells. NO also counteracts platelet adhesion and aggregation. NO is released from endothelial cells by the action of acetylcholine (ACh). Failure of the vascular endothelium to elicit NO-mediated vasodilatation may be due to decreased formation of NO, increased degradation of NO and/or decreased biological sensitivity to NO. Irrespective of the mechanism this is referred to as endothelial dysfunction.
The vascular endothelium is also the site of formation of other vasodilator agents (e.g. prostacyclin, endothelium-derived hyperpolarizing factor), as well as vasoconstrictive factors (e.g. thromboxane A2, endothelin).
Endothelium dysfunction is highly relevant to vascular disease and occurs chiefly as a consequence of disturbances in the L-arginine/NO pathway.
Its occurrence in type 2 diabetes, for example, is extensively supported by both in vitro and in vivo studies (Cohen, 1993; Watts, 1998). Indeed, endothelial dysfunction may be the initiating event in the process of atherosclerosis eventually resulting in clinical coronary artery disease. In hypercholesterolemic subjects, impaired endothelium-dependent vasodilatation is evidenced before the development of atherosclerosis. In patients with type 2 diabetes endothelial function is abnormal even in the absence of elevated plasma LDL cholesterol concentration.
Endothelial dysfunction in diabetes may have implications not only for coronary artery disease, but also for peripheral vascular disease and retinopathy. Experimental and clinical studies support the concept that dyslipidemia (in particular increased circulatory concentrations of modified, small dense LDL), as well as hyperoxidative stress, are closely related to the development of endothelial dysfunction as a consequence of changes in the disposal of nitric oxide NO.
Oxidative stress represents a challenge to normal bodily functions. It may arise from an increase in exposure to free radicals/oxidants or may be a result of a decrease in anti-oxidant capacity. Oxidative stress is caused by reactive oxygen species which can be of both endogenous or exogenous origin. Endogenous sources of free radicals, such as the superoxide anion O2.−, include endothelial cells, activated neutrophils and mitochondria. The term reactive oxygen species includes not only oxygen-centred radicals (e.g. superoxide and hydroxyl), but also non-radical derivatives of oxygen (H2O2), singulet oxygen and HOCl. In diabetes, as well as in myocardial infarction, stroke and inflammation, there is an increase in plasma levels of lipid hydroperoxides which are formed through a free radical-mediated mechanism from polyunsaturated fatty acids.
Accordingly, given the association between oxidative stress, endothelial dysfunction and a range of important disorders there is a need to provide an effective treatment for endothelial dysfunction caused by oxidative stress. In particular, type 2 diabetes is associated with a markedly increased risk of cardiovascular disease, its major complication.
Treatments have not been shown to be effective. There is a major need for new preventative and therapeutic strategies for cardiovascular disease.